Synthesis and biology of a 7-nitro-2,1,3-benzoxadiazol-4-yl derivative of 2-phenylindole-3-acetamide: A fluorescent probe for the peripheral-type benzodiazepine receptor
Synthesis and biology of a 7-nitro-2,1,3-benzoxadiazol-4-yl derivative of 2-phenylindole-3-acetamide: A fluorescent probe for the peripheral-type benzodiazepine receptor
复制标题
DOI：
10.1021/jm970220w
复制
发表时间：
1997-08-01
影响因子：
7.3
通讯作者：
Papadopoulos, V
中科院分区：
文献类型：
--
作者：
Kozikowski, AP;Kotoula, M;Papadopoulos, V
苯二氮卓类药物是最常用的处方药之一，因为它们通过调节中枢神经系统中γ-氨基丁酸受体的活性来介导缓解焦虑的药理作用。外周型苯二氮卓受体（PBR）是苯二氮卓类药物的另一类结合位点，与上述神经递质受体不同。PBR最初被发现是因为它以相对高的亲和力结合苯二氮卓类地西泮。2进一步的研究表明，除了苯并二氮杂卓类化合物，PBR与其他类别的有机化合物，如异喹啉，3咪唑并吡啶，4吲哚衍生物，5和吡咯并苯并氧氮杂卓类化合物具有高亲和力。6除了这些药物配体，多肽地西泮结合抑制剂7卟啉8和苯二氮卓样分子9已被鉴定为内源性PBR配体。PBR虽然存在于所有检查的组织中，但发现在产生类固醇的组织（如肾上腺、睾丸、卵巢、胎盘和脑组织）中以特别高的密度发生。在这些细胞中，发现PBR主要位于线粒体中，更具体地说，位于线粒体外膜中。11 PBR的非线粒体位置也在各种组织中被描述。12一种18 kDa的异喹啉结合蛋白被鉴定为PBR，并进行克隆和表达。13基于PBR配体的药理学作用和18 kDa异喹啉结合蛋白的组织特异性细胞和亚细胞定位，PBR已被证明参与许多功能，包括类固醇生物合成、线粒体呼吸、血红素生物合成、钙通道调节、细胞增殖和分化以及免疫调节。10，12从这些功能中，PBR在类固醇生成中的作用是相当明确的。使用肾上腺，14睾丸Leydig，15卵巢颗粒，16胎盘，17和脑胶质细胞18，它已被证明，PBR是一个功能组件的类固醇生成机制介导的胆固醇交付从外部到内部线粒体膜。19进一步的研究表明，在体内，肾上腺皮质激素诱导的肾上腺PBR水平降低导致循环糖皮质激素水平降低。20此外，靶向破坏类固醇生成细胞中的PBR基因导致胆固醇转运至线粒体内膜的抑制和类固醇生物合成的停滞。因此，PBR为开发可用于调节外周和中枢神经系统中类固醇合成以及调节上述PBR依赖性功能的化合物提供了有吸引力的靶分子。使用高亲和力配体、针对18 kDa PBR蛋白的整个分子或片段开发的抗血清和cDNA探针，进行上述关于固定细胞或分离的亚细胞级分中PBR的结构和功能的定位和表征的研究3r 20。考虑到与抗血清特异性和灵敏度以及亚细胞分级分离相关的问题，人们可能会认为所获得的结果可能不代表活细胞中的实际情况。我们在本文中报道了合成、表征和生物学
Benzodiazepines are among the most highly prescribed drugs due to their pharmacological action of relieving anxiety mediated through modulating the activity of γ-aminobutyric acid receptors in the central nervous system. 1 The peripheral-type benzodiazepine receptor (PBR) is another class of binding sites for benzodiazepines distinct from the aforementioned neurotransmitter receptors. The PBR was originally discovered because it binds the benzodiazepine diazepam with relatively high affinity. 2 Further studies demonstrated that in addition to the benzodiazepines, PBR binds with high affinity other classes of organic compounds, such as isoquinolines, 3 imidazopyridines, 4 indole derivatives, 5 and pyrrolobenzoxazepines. 6 In addition to these drug ligands, the polypeptide diazepam binding inhibitor, 7 porphyrins, 8 and benzodiazepine-like molecules9 have been identified as endogenous PBR ligands. The PBR, although present in all tissues examined, was found to occur in particularly high density in steroid-producing tissues, such as adrenal, testis, ovary, placenta, and brain tissues. 10 In these cells, the PBR was found to be localized primarily in the mitochondria and more specifically in the outer mitochondrial membrane. 11 Nonmitochondrial locations of PBR have also been described in various tissues. 12 An 18 kDa isoquinoline-binding protein was identified as PBR, cloned, and expressed. 13 On the basis of the pharmacological effects of PBR ligands and the tissue-specific cellular and subcellular localization of the 18 kDa isoquinoline binding protein, the PBR has been shown to be involved in numerous functions including steroid biosynthesis, mitochondrial respiration, heme biosynthesis, calcium channel modulation, cell proliferation and differentiation, and immunomodulation. 10, 12 From these functions the role of PBR in steroidogenesis is fairly well established. Using adrenal, 14 testis Leydig, 15 ovarian granulosa, 16 placenta, 17 and brain glia18 cells, it has been demonstrated that the PBR is a functional component of the steroidogenic machinery mediating cholesterol delivery from the outer to the inner mitochondrial membrane. 19 Further studies demonstrated that pharmacologically induced reduction of adrenal PBR levels in vivo resulted in decreased circulating glucocorticoid levels. 20 In addition, targeted disruption of the PBR gene in steroidogenic cells resulted in inhibition of cholesterol transport to the inner mitochondrial membrane and arrest of steroid biosynthesis. 21 Thus, the PBR provides an attractive target molecule for the development of compounds which may be used for the regulation of steroid synthesis in the periphery and the central nervous system and for the regulation of the abovementioned PBR-dependent functions. The studies described above on the localization and characterization of the structure and function of the PBR in fixed cells or isolated subcellular fractions3r20 were performed using high-affinity ligands, antisera developed against the entire molecule or fragments of the 18 kDa PBR protein, and cDNA probes. Considering the problems associated with antiserum specificity and sensitivity as well as with subcellular fractionation, one could argue that the results obtained may not represent the actual situation in a living cell. We report herein the synthesis, characterization, and biologic